Cholesterol is a lipid molecule, which is biosynthesized by animal cells or absorbed from food such as egg yolks, meat, poultry, fish, and dairy products. It is an essential component to cell membranes and it is required for cell integrity and fluidity. In particular, cholesterol is a precursor for the biosynthesis of steroid hormones, bile acid and vitamin D.
Cholesterol is transported through bloodstream as lipoproteins, which are made of lipids on the inside and proteins on the outside. These lipoproteins are divided into five major lipoproteins: chylomicrons, very low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), low-density lipoproteins (LDL) and high-density lipoproteins (HDL).
Amongst those lipoproteins, LDL is often referred to as “bad” cholesterol, since high LDL level leads to a buildup of cholesterol deposits in arteries. On the other hand, HDL is considered as “good” cholesterol, because it carries cholesterol from all parts of the body back to the liver, which in turn eliminates the excess cholesterol from the body, therefore HDL has anti-atherogenic properties.
High blood cholesterol or hypercholesterolemia is a condition characterized by an excess of cholesterol in blood. Although, this condition usually has no signs or symptoms, individuals with high blood cholesterol have a greater chance to develop cardiovascular disorders (cardiovascular disorder). Guidelines regarding cholesterol levels are available recommending [total cholesterol] within 150-199 mg/dL (3.88-5.15 mmol/L), [LDL] levels below 130 mg/dL (<3.36 mmol/L), and [HDL] above 40 mg/dL (>1.04 mmol/L) (The Merck Manual of Diagnosis and Therapy, 2011).
According to the World Health Organization (WHO), cardiovascular disorder is the leading cause of death globally, with an estimated 17.5 million deaths in 2012.
One particular type of cardiovascular disorder is atherosclerosis, which is a condition where a plaque made up of cholesterol, fat, calcium, and other blood components builds up inside arteries, in particular in coronary arteries. Over time, this plaque grows and hardens, thus limiting blood circulation and oxygen supply to the heart leading eventually to angina or heart attack, which may be fatal.
Therefore, reducing [LDL] levels and increasing [HDL] levels would be beneficial in reducing cardiovascular disorder (Barter, 2011; Chapman, 2006).
In rheumatoid arthritis (RA) patients, it has been observed that the [total cholesterol] level is lower. It could therefore be expected that low cholesterol levels would render RA patients less subject to cardiovascular disorder. However, against all expectations, these same patients having a high inflammatory burden were found to be at heightened cardiovascular disorder risk. This heightened cardiovascular disorder risk with low [LDL] and cholesterol levels has been branded the ‘RA-lipid paradox’ (Robertson et al., 2013). In particular, it has been observed that not only do RA patients suffer from low lipid levels, but in addition the [LDL] proportion is higher compared to [HDL] (Kumar and Armstrong, 2008).
With the numerous therapies being developed to treat RA, many clinical studies have been conducted, and the relationship between inflammation and lipid profile has been investigated, but remains unclear. In particular, upon treatment of inflammation, it was observed that lipid levels returned to normality, albeit with a higher [LDL] proportion compared to [HDL] (Navarro-Millán et al., 2013), therefore potentially increasing the cardiovascular disorder risk again.
The association between moderately elevated CRP levels and an increased risk for development of cardiovascular disease is well established (Nilsson, 2005). Moreover, the rise in blood cholesterol in patients with inflammation after treatment has been argued to be associated with the resolution of inflammation and reduction in CRP. For this reason, CRP has emerged as an interesting and potentially clinically useful marker for increased cardiovascular risk (Nilsson, 2005; Ridker et al., 2002). Guidelines regarding the levels of CRP associated to the rise in cardiovascular disorders have also been issued setting normal CRP levels at <0.5 mg/dL (The Merck Manual of Diagnosis and Therapy, 2011). Similarly and independently, heightened [LDL] has been identified as a predictor for cardiovascular disease (Song et al., 2015). Therefore, it would be particularly beneficial if anti-inflammatory therapy would not only increase abnormally low cholesterol levels in patients, but if such therapy would do so with a preferential increase in [HDL], relative to [LDL] and [total cholesterol].
In addition to CRP, additional biomarkers which may play a role in cardiovascular disorders, particularly atherogenesis, have been identified in the recent years (Chait et al., 2005). Such biomarkers include Serum Amyloid A (SAA), secretory phospholipase A2 (sPLA2), Apolipoprotein A-I (ApoA-1), or paraoxonase 1 (PON1).
SAA is carried by lipoproteins, in particular HDL, and its levels are markedly raised during acute inflammatory episodes, but also in conditions associated with increased cardiovascular risks including obesity, insulin resistance, diabetes, metabolic syndrome, and RA. High levels of SAA may contribute to the stimulation of monocyte adhesion and chemotaxis into the artery wall cells, and increased delivery of cholesterol to artery cell walls, thus suggesting that SAA is a mediator of atherosclerosis and a marker for cardiovascular disorders (Chait et al., 2005).
sPLA2 is present in artery walls, and hydrolyses phospholipids in both LDL and HDL; but it also converts LDL into particles associated with increased risk of cardiovascular disorders (Chait et al., 2005).
ApoA-I is the major component of HDL, therefore, low levels of ApoA-I are correlated to low HDL levels, and thereby higher cardiovascular risks (Chait et al., 2005).
PON1 belongs to the paraoxonase family, which protects cells from damages by organophosphate toxins, and is synthesized by the liver, from where it is transported into the plasma by HDL. In turn, HDL associated PON1 inhibits lipid peroxidation, which may prevent atherosclerosis (Chait et al., 2005).
In fighting RA, Janus kinases (JAKs) inhibitors have been developed. JAKs are cytoplasmic tyrosine kinases that transduce cytokine signaling from membrane receptors to STAT transcription factors. Four JAK family members have been described, JAK1, JAK2, JAK3 and TYK2. Upon binding of the cytokine to its receptor, JAK family members auto- and/or transphosphorylate each other, followed by phosphorylation of STATs that then migrate to the nucleus to modulate transcription. JAK-STAT intracellular signal transduction serves the interferons, most interleukins, as well as a variety of cytokines and endocrine factors such as EPO, TPO, GH, OSM, LIF, CNTF, GM-CSF and PRL (Vainchenker W. et al. (2008)).
The combination of genetic models and small molecule JAK inhibitor research revealed the therapeutic potential of inhibition of several JAKs.
JAK1 is a target in the immuno-inflammatory disease area. JAK1 heterodimerizes with the other JAKs to transduce cytokine-driven pro-inflammatory signaling. Therefore, inhibition of JAK1 is of interest for immuno-inflammatory diseases with pathology-associated cytokines that use JAK1 signaling, such as IL-6, IL-4, IL-9, IL-15, IL-21, or IFNgamma, as well as for other diseases driven by JAK-mediated signal transduction. The compound according to Formula I, cyclopropanecarboxylic acid {5-[4-(1,1-dioxo-thiomorpholin-4-ylmethyl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2yl}-amide (Compound 1), is disclosed in WO2010/149769 (Menet and Smits, 2010) and has the chemical structure shown below:

Compound 1 is a JAK inhibitor, more particularly a JAK1 inhibitor, and useful in the treatment of inflammatory conditions, autoimmune diseases, proliferative diseases, allergy, transplant rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IL6 or interferons.
However, whereas JAK inhibitors are useful and effective molecules in the treatment of RA, or inflammatory bowel disorders (IBD) one drawback to the use of these compounds that has been reported is hypercholesterolemia (O'Shea et al., 2013; O'Shea and Plenge, 2012).
The identification and development of new agents for the treatment of cardiovascular disorders and/or dyslipidemia would be highly desirable, both for patients suffering from inflammatory disorders, e.g. RA patients, and non-inflamed patients alike. In particular, there is a need for anti-inflammatory therapies which not only restore abnormal lipid profile levels in patients to normal recommended values as defined herein, but which do so with a preferential increase in [HDL], relative to [LDL].